Diabetic nephropathy
12/21 中西醫聯合討論會 Nephro Fellow 1 潘恆之
Introduction
Introduction
• Diabetic nephropathy occurs in type 1, type 2
diabetes mellitus and other secondary forms
of diabetes mellitus
• A glomerulopathy defined by characteristic
structural and functional changes：mesangial
expansion, glomerular basement membrane
thickening, and glomerular sclerosis
• Major clinical manifestation are albuminuria,
progressive chronic kidney disease, and less
often hematuria.
~ American Journal of Kidney disease vol 44, No 1, July 2004
Pathogenesis
• Glomerulosclerosis result form :
a. Intraglomerular hypertension due to renal
vasodilatation
b. Ischemic injury induced by hyaline narrowing of
the vessels supplying the glomeruli
 and why renal vasodilatation and glomeruli
vessels hyaline narrowing ????
Pathogenesis
• There appear to be some different pathogenetic
processes：
1. Glomerular hyperfiltration
2. Hyperglycemia and AGEs
3. Prorenin
4. Cytokines
5. Nephrin expression
6. Impaired podocyte-specific insulin signaling
Glomerular hyperfiltration
• In an animal model of diabetic nephropathy :
a. BP, intra-renal Ang II level, and type IV collagen
expression are higher in prediabetic rats
b. Renin-angiotensin system blockade reduced
intrarenal Ang II, type IV collagen expression,
risk of proteinuria and improved glomerular
structure.
Temporary angiotensin II blockade at the prediabetic stage attenuates the development
of renal injury in type 2 diabetic rats.
J Am Soc Nephrol. 2005;16(3):703.
Glomerular hyperfiltration
=> glomerular hypertension and hyperfiltration have
roles in diabetic nephropathy
=> Antagonizing the profibrotic effects of angiotensin
II has benefit for diabetic nephropathy
Temporary angiotensin II blockade at the prediabetic stage attenuates the development
of renal injury in type 2 diabetic rats.
J Am Soc Nephrol. 2005;16(3):703.
Hyperglycemia and AGEs
(advanced glycation end products)
• Hyperglycemia stimulates mesangial expansion and
mesangial cell apoptosis via increased matrix
production or glycation of matrix protein
• Excess glucose combines with free amino acids on
circulating or tissue protein  circulating and tissue
AGE accumulation  crosslinking with collagen 
renal and microvascular complication
• Hyperglycemia activates protein kinase C 
upregulation of heparanase expression as a decrease
in cell surface heparan sulfate  glomerular
basement membrane permeability to albumin
Increased expression of heparanase in overt diabetic nephropathy.
Kidney Int. 2006;70(12):2100.
Cytokines
• Activation of cytokines, profibrotic elements,
inflammation, and VEGF maybe involved in the matrix
accumulation in diabetic nephropathy.
1. Hyperglycemia stimulates VEGF expression
 VEGF blockde improves albuminuria in diabetic
nephropathy
Blockade of vascular endothelial growth factor ameliorates diabetic albuminuria in mice.
J Am Soc Nephrol. 2006;17(11):3093.
2. Hyperglycemia induced decrease in activated protein
C --> structural lesion of diabetic nephropathy
and worsens proteinuria in mice
Activated protein C protects against diabetic nephropathy by inhibiting endothelial and
podocyte apoptosis.
Nat Med. 2007;13(11):1349.
Cytokines
3. TGF-β contributes to cellular hypertrophy and
enhances collagen synthesis
 hyperglycemia increases expression of TGF-β in
the glomeruli and matrix protein
Molecular mechanisms of diabetic renal hypertrophy.
Kidney Int. 1999;56(2):393.
4. Renal bone morphogenic protein-7 (BMP-7) counter
the profibrogenic actions of TGF-β
 diabetes is associated with decreased expression
of BMP-7
Renal bone morphogenetic protein-7 protects against diabetic nephropathy.
J Am Soc Nephrol. 2006;17(9):2504.
Prorenin
• Prorenin binds to a specific tissue receptor that
promotes activation of the mitogen-activated protein
kinases(MAPK)p44/p42A
 Prolonged prorenin receptor blockade abolished
MAPK activation prevent diabetic nephropathy
despite an unaltered increase in angiotension II
activity
Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic
angiotensin II type 1a receptor-deficient mice.
J Am Soc Nephrol. 2006;17(7):1950.
Nephrin expression
• Impaired in diabetic nephropathy and congenital
mutations  result in severe nephrotic syndrome
• Diabetic nephropathy has markedly lower renal
nephrin expression and fewer electron dense slit
diaphram than minimal change and controls 
podocin and CD2AP expression are similar amont the
three groups.
Selective impairment of gene expression and assembly of nephrin in human diabetic
nephropathy.
Kidney Int. 2004;65(6):2193.
Schematic of the slit diaphragm and other important proteins involved in maintaining foot
process assembly.
Quaggin S E , Kreidberg J A Development 2008;135:609620
Impaired podocyte-specific insulin
signaling
• Mouse models (podocyte-specific insulin receptor
deficiency):
In the absence of hyperglycemia, affected mice
developed albuminuria, effacement of foot
processes, apoptosis, glomerular basement
membrane thickening, accumulation of mesengial
matrix and glomerulosclerosis
 activation of the insulin receptor remodeling
MAPK 42/44 and Phosphatidylinositol 3 (PI3)
kinase signaling pathways  proteinuria decrease
clinical implications of basic research
Proteinuria, the Podocyte, and Insulin Resistance
N Engl J Med 2010; 363:2068-2069 November 18, 2010
Risk factors
• Family history of diabetes
• Black race, Mexican-American or Pima Indian
ancestry
• Higher systemic blood pressures
• Poor glycemic control
• Smoking
• Oral contraceptives
• Obesity
• Old age
Treatment
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Glycemic control
Blood pressure control
Lipid control
Salt and protein restriction
Weight reduction
Angiotensin inhibition
Calcium channel blocker
PPAR-gamma agonists
Other agents
Glycemic control
• Delay the development of elevated albumin excretion,
slow the rate of progressive renal injury
• Reverse the glomerular hypertrophy and hyperfiltration,
improves glomerular structure :
a. mesengial and mesengial matrix volume decrease
b. glomerular and tubular basement membranes
return to normal,
nodular glomerular
lesions disappear
c. tubular atrophy
improves
N Engl J Med 1993;329:977
Diabetic nephropathy reverses after pancreas transplantation
N Engl J Med 1998; 339:69
Blood pressure control
• United Kingdom Prospective Diabetes Study (UKPDS) :
a. SBP decrease 10 mmHg  12% risk reduction in
diabetic complication (P<0.001)
b. the lowest risk occurred at SBP below 120mmHg
Blood pressure control
•Irbesartan Diabetic Nephropathy Trial (IDNT) :
a. progressively lower SBP to 120mmHg was associated
with decreased cardiovascular death, heart failure,
serum creatinine doubling and ESRD risk
b. BP < 120/85 mmHg increased the risk of all-cause
mortality, cardiovascular death and heart failure
Strict BP control is important for preventing
progression of diabetic nephropathy in type 2 DM,
but the optimal lower limit for BP is unclear.
Lipid control
• Elevation in lipid levels lead to promote systemic
atherosclerosis and glomerulosclerosis in CKD patient.
• In type 1 diabetes mellitus patient, plasma
cholesterol > 220mg/dL was an important risk factor
for progressive renal disease, particularly if the
diastolic pressure > 85 mmHg.
Hypercholesterolemia--a determinant of renal function loss and deaths in IDDM
patients with nephropathy.
Kidney Int Suppl. 1994;45:S125.
Lipid control
• The rate of progression from normal albumin
excretion to microalbuminuria decreases with
fenofibrate (a peroxisome proliferator activated
receptor (PPAR)-alpha specific ligand)
* Possible mechanisms of fenofibrate benefit :
PPAR-α activity --> inflammation and
production of type 1 collagen in mesangial cells
PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice.
Kidney Int. 2006;69(9):1511.
Salt restriction
• High salt intake blunt the antiproteinuric effects of
angiotensin inhibitors
• Salt restriction and/or diuretics enhance the effect of
renin-angiotensin blockade on proteinuria.
• Salt restriction to < 70 meq /day enhance the
antiproteinuric effects of ARB in T2DM patient
=> If it is difficult to achieve:
a. restrict sodium intake to 100 < 100meq/d
b. give diuretic partially corrects the loss of
antiproteinuric effect due to high sodium intake
Protein restriction
• Protein reduction reduce the rate of progression in
DM patient with overt nerphropathy.
=> Suggest: avoid a high protein diet (1g/kg/d)
Effect of dietary protein restriction on prognosis in patients with diabetic
nephropathy.
Kidney Int. 2002;62(1):220.
Weight reduction
• Marked decreases in proteinuria may be observed in
obese diabetics who lose weight
• Proteinuria significantly decreased at five months
among dieters versus the non-dieters control group (
mean weight loss of 4% in the diet group)
• No significant differences in renal function were
reported in either group.
Beneficial effects of weight loss in overweight patients with chronic
proteinuric nephropathies.
Am J Kidney Dis. 2003;41(2):319.
the length of follow-up was probably too short to
have observed renoprotection effect.
Angiotensin inhibition
• Primary prevention for diabetic nephropathy
• Preservation of renal function
Angiotensin inhibition
Primary prevention for diabetic nephropathy
* Diabetes induces renal vasodilation,
intraglomerular hypertension and glomerular
hypertrophy
• ACEI and ARB reduce intrarenal vascular resistance
and inhibit TGF-β
 reduce intraglomerular pressure, minimize
glomerular injury, inhibit cellular hypertrophy
and collagen synthesis
Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in
patients with type 2 diabetes.
J Am Soc Nephrol. 2005;16(4):1135.
Captopril reduces (intra)renal vascular resistance in patients with type 2 diabetes
Kidney Int 1989;36:526.
Angiotensin inhibition
• Preservation of renal function
* T1DM:
a. ACEI decreases albumin excretion, CKD
progression rate, risk of overt nephropathy,
ESRD or death.
NEJM 1993;329:1456.
Angiotensin inhibition
b. ACEI + ARB produces a greater reduction in
protein excretion (in 2 short-term studies, 8 wks)
--- due to better BP control ???
Dual blockade of the renin-angiotensin system versus maximal recommended dose
of ACE inhibition in diabetic nephropathy.
Kidney Int. 2003;63(5):1874.
* T2DM – renal protection with ARBs
a. Irbesartan Diabetic Nephropathy Trial (IDNT):
@Irbesartan has lower risk (23%) in doubling of Scr,
proteinuria, ESRD or death than amlodipine (and placebo)
@Renal failure risk doubles with each doubling of
baseline protein excretion
@The renal outcomes are best at SBP <134mmHg
b. RENAAL study:
@Losartan reduced the albuminuia, incidence of
creatinine doubling and ESRD by 25% and 28%
@ SBP every 10mmHg => ESRD or death risk 6.7%
@ Albuminuria every 50% => CV risk 18%, ESRD risk
@ Baseline retinopathy has poor renal outcome
•Both of studies show ARB has clear benefits in T2DM
patients with overt nephropathy
•ARB had significant reductions in the development of
heart faliure. However, CV mortality has no obvious
reduction.
 too short duration of the studies??
* T2DM – renal protection with ACEIs
a. ADVANCE trial :
perindopril-indapamide combination vs placebo:
@ significant reduction of new onset microalbuminuria
or worsening of protienuria (19.6% vs 23.6% )
@ significant decrease in mean BP (5.6/2.2 mmHg)
@ no significant defference in CKD progression
=> the renal benefits are due to the ACEI or BP control ??
b. DETAIL trial :
enalapril vs. telmisartan vs. placebo
@ at 5 yrs, enalapril has smaller GFR decline (NS)
@ similar findings of BP, Scr, albuminuria, ESRD, CV
events and mortality.
ACEIs are at least as effective as ARBs in diabetic
patient with microalbuminuria
ACEIs or ARBs has renoprotection in patient with
diabetic nephropathy (progress slowly)
1/3 of renoprotective effect with ACEI or ARB is due to
proteinuria reduction in first 12 months of therapy
• ACEI + ARB ???
* small studies –
decrease proteinuria in T1DM & T2DM
* ONTARGET study –
proteinuria and GFR =>
ESRD and mortality rate =>
CKD progression => NS
•ARB + aliskiren
@ AVOID trial – aliskiren + losartan vs. losartan
* aliskiren + losartan has 20% greater reduction
in proteinuria (no significant on BP)
* role of aliskiren in preventing CKD progression ??
Aldosterone antagonism
• small study – 81 patient, f/u 48weeks
lisinopril + sprionolactone or losartan or placebo
* spironolactone + lisinopril –urine ACR decre 34% (S)
losartan + lisinopril – urine ACR 17% (NS)
* no long term data about CKD progression with
ACEI/ARB + aldosterone blockade
* Serum pottasium is significant high in both group
Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study.
Am J Kidney Dis. 2005;46(1):45.
• Another small studies – 268 patient, f/u 40wks
ACEI + eplerenone or placebo
 eplerenone has additive antiproteinuria effect,
similar hyperkalemia rate
Beneficial impact of spironolactone in diabetic nephropathy.
Kidney Int. 2005;68(6):2829.
• Aldosterone antagonists appear to reduce
proteinuria when used alone or combination with
ACEI/ARB in type 1 and type 2 diabetes.
=> suggestion : avoid NSAID, combine kaliuretic
diuretic therapy
Calcium channel blocker
• Non-dihydropyridine calcium channel blockers slow
the rate of progression of diabetic nephropathy
* diltiazem and verapamil is as effective as
ACEI/ARB in lowering protein excretion in diabetic
patients
* the antiproteinuric effects of verapamil and ACEI
may be addictive
* However, diltiazem increases tubulointerstitial
fibrosis andglobal glomerulosclerosis. The effect
was prevented by combined an ACE inhibitor.
Effects of different antihypertensive treatments on morphologic progression of diabetic
nephropathy in uninephrectomized dogs.
Kidney Int. 1994;46(1):161.
Antihypertensives and urinary
protein excretion in diabetic
nephropathy
Kidney Int. 1992;46(1):161.
Superior antiproteinuric effect with combination of antihypertensive therapy
Kidney Int. 1998;57(1):193.
Superior antiproteinuric effect with combination of antihypertensive therapy
Kidney Int. 1993;51(5):129.
• The antiproteinuric mechanism of
nondihydropyridine calcium channel blockers:
1. possible reduction in intraglomerular pressure
2. reduce the associated glomerular hypertrophy
3. diltiazem may improve glomerular size
permselectivity.
Differential effects of calcium channel blockers on size selectivity of proteinuria in
diabetic glomerulopathy.
Kidney Int. 1998;54(3):889.
* Uncertain clinical relevance.
* The efficacy in the preservation of renal fucntion in
relation to ACEI has not yet been evaluated in
humans
• Dihydropyridine calcium channel blockers ( such as
amlodipine, nifedipine, nitrendipine) have a variable
effect ranging from increased protein excretion to no
effect to a fall in protein excretion in different studies.
• Beta-blockers have shown a variable response of
protein excretion decrease
PPAR-ϒ agonists
• Peroxisome proliferator-activated receptors (PPAR)
which are ligand-activated transcritption factors,
have a role in regulating adipogenesis, lipid
metabolism, insulin sensitivity, inflammation, blood
pressure, and development of T2DM nephropathy.
• PPAR-ϒ agonists, such as the thiazolidinediones (eg,
pioglitazone and rosiglitazone), induce reductions in
fibrosis, mesangial cell proliferation, and
inflammation in animal models of diabetic
nephropathy .
Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.
J Am Soc Nephrol. 2008;19(1):182.
PPAR-ϒ agonists
• In small studies, PPAR-gamma agonists reduce urinary
albumin excretion at various stages of nephropathy
and to reduce blood pressure.
 Larger studies are required to detect a renoprotective effect
• A post hoc analysis of the PROACTIVE trial failed to
show a definitive benefit on cardiovascular risk
reduction with pioglitazone in people with stage 3 or
higher nephropathy
Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.
J Am Soc Nephrol. 2008;19(1):182.
Other agents
Bardoxolone methyl
• An antioxidant inflammatory modulator that may
also have prostaglandin-like effects. It has been
beneficial in animal models of drug-induced or
ischemic acute kidney injury.
• In the Bardoxolone Methyl Treatment: Renal
Function in CKD/Type 2 Diabetes (BEAM) trial,
Bardoxolone methyl therapy at all three doses
significantly increased eGFR at 52 weeks of follow-up
by 6 to 10 mL/min per 1.73 m2, while placebo
therapy had no effect.
Bardoxolone methyl
• The disadvantages of Bardoxolone methyl therapy :
a. significantly increased albuminuria
 The change in albuminuria was significantly
correlated with the change in eGFR.
 Increase in eGFR may be mediated by
increase in intraglomerular hydrostatic pressure
b. significantly increased adverse events -muscle spasms, nausea, and SBP 2~4 mmHg.
Bardoxolone methyl and kidney function in CKD with type 2 diabetes.
N Engl J Med. 2011;365(4):327.
Other agents
• limited data, including a meta-analysis, suggest that
pentoxifylline lowers proteinuria and may have
similar antiproteinuric effects as ACE inhibitors.
The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis.
Am J Kidney Dis. 2008;52(3):454.
• Endothelin receptor antagonists, protein kinase C
inhibitors,), sulodexide, and fish oil.
• There are insufficient data on any of these agents to
advocate their use for the treatment or prevention of
diabetic nephropathy.
Fenofibrate reduces progression to microalbuminuria over 3 years in a placebocontrolled study in type 2 diabetes: results from the Diabetes
Am J Kidney Dis. 2005;45(3):485.
Summary of treatment
• Primary prevention for diabetic nephropathy：
Angiotensin inhibition
Strict glycemic control
PPAR –gamma agonist ?
• Preservation of renal function：
Antihypertensive therapy (particularly with an ACEI)
ARB/ACEI (T2DM with overt nephropathy)
Protein restriction (T1DM with overt nephropathy) ?
Combined therapy
• Steno type 2 diabetes study :
• mean follow-up 7.8 yrs, intensive therapy reduced
albumin excretion, microvascular and macrovascular
disease
• GFR fall to the same degree in both groups.
120/75 mmHg vs 130/80mmHg
Aggressive blood pressure control has benefits in chronic kidney disease patient
NEJM. 1994;68(6):2829.
Recommendations
• Type 1 DM:
a. check urine ACR yearly after the first 5 yrs.
If positive  follow up 3-6 m x 2 (at least)
 confirm the diagnosis by at least 2 of 3
positive samples
b. strict glycemic and lipid control
c. give ACEI if BP > 130/80 mmHg or
persistent microalbuminuria
d. give loop diuretics to attain dry weight
Recommendations
e. If BP > 130/80 mmHg or proteinuria >500 ~
1000mg/d under ACEI treatment
 give nondihydropyridine calcium channel
blocker (diltiazem/verapamil) or long-acting
dihydropyridine calcium channel blocker if
the patient already being treated with a betablocker
f. If overt nephropathy  take sodium < 90meq/d
to achieve maximal antiproteinuric effects with
ACEI
g. Avoid high protein diet ( 1g/kg/d)
Recommendations
• Type 2 DM:
a. give a ARB or ACEI ( not combine them !!)
b. if BP > 130/80mmHg or proteinuria > 500 ~
1000mg/d  give diltiazem or verapamil
c. if edema or renal insufficiency  give loop
diuretic to attain dry weight
d. if overt nephropathy  take sodium < 90meq/d
to achieve maximal antiproteinuric effects with
ACEI
e. Avoid high protein diet ( 1g/kg/d)
Thanks for your attention !!